# Central tolerance mechanisms in B-cell malignancies

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $402,275

## Abstract

ABSTRACT
Humans produce each day ~100 million autoreactive B-cells that express potentially harmful autoantibodies.
This burden of autoreactive B-cells requires a powerful purging mechanism, termed central tolerance, to prevent
autoimmune disease. During the previous period of this R01, we discovered that central tolerance mechanisms
not only remove newly formed autoreactive B-cells but also eliminate B-cell tumors that originate from early
stages of B-cell development, namely B-cell acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL)
and chronic lymphocytic leukemia (CLL). Hence, central tolerance could represent a previously unrecognized
vulnerability in B-cell tumors that is orthogonal to conventional mechanisms of drug-resistance.
B-ALL represents the most frequent type of cancer in children. MCL and CLL are common in adults and remain
incurable diseases. Small molecule inhibitors of kinases downstream of the B-cell receptor (BCR) have
substantially extended survival, although treatment with kinase-inhibitors alone invariably selects for drug-
resistance and relapse. Approximately 1.4 million people in the US are currently living with or recovering from B-
cell malignancies (SEER), highlighting the importance of efforts to reduce toxicity and minimize late effects.
Central tolerance mechanisms sense and eliminate transformed B-cells based on pathological signaling: Normal
antigen encounter results in a short transient pulse of PI3K-activation, slow Ca2+-oscillations, tonic NF-B
activation and positive selection. We discovered two distinctive features of pathological signaling that
initiate central tolerance mechanisms:
  Persistent PI3K-signaling (Aim 1) forces aberrant increases of cell size, causing ATP-depletion (AMPK-
 phosphorylation) and energy crisis.
  High-frequency Ca2+-oscillations (Aim 2) in pathological B-cells are decoded by NFAT instead of NF-
 B, induce NFAT-dependent anergy and cell death.
Here we test the overarching hypothesis that central tolerance mechanisms represent a novel class of
therapeutic targets in B-cell tumors that arise from early B-cell development (B-ALL, CLL and MCL).
Given their B-cell intrinsic activity, targeting of central tolerance mechanisms is expected to have minimal side-
effects.

## Key facts

- **NIH application ID:** 10694016
- **Project number:** 5R01CA157644-14
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Markus Muschen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $402,275
- **Award type:** 5
- **Project period:** 2011-06-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10694016

## Citation

> US National Institutes of Health, RePORTER application 10694016, Central tolerance mechanisms in B-cell malignancies (5R01CA157644-14). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10694016. Licensed CC0.

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